Methods and devices for activating brown adipose tissue using electrical energy

ABSTRACT

Methods and devices are provided for activating brown adipose tissue (BAT) using electrical energy. In general, the methods and devices can facilitate activation of BAT to increase thermogenesis. The BAT can be activated by applying an electrical signal thereto that can be configured to target sympathetic nerves that can directly innervate the BAT. The electrical signal can be configured to target the sympathetic nerves using fiber diameter selectivity. In other words, the electrical signal can be configured to activate nerve fibers having a first diameter without activating nerve fibers having diameters different than the first diameter. Sympathetic nerves include postganglionic unmyelinated, small diameter fibers, while parasympathetic nerves that can directly innervate BAT include preganglionic myelinated, larger diameter fibers. The electrical signal can be configured to target and activate the postganglionic unmyelinated, small diameter fibers without activating the preganglionic myelinated, larger diameter fibers.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. patent application Ser.No. 16/445,725 entitled “Methods And Devices For Activating BrownAdipose Tissue Using Electrical Energy” filed Jun. 19, 2019, whichclaims priority to U.S. patent application Ser. No. 16/197,786 entitled“Methods And Devices For Activating Brown Adipose Tissue UsingElectrical Energy” (now U.S. Pat. No. 10,391,298) filed Nov. 21, 2018,which claims priority to U.S. patent application Ser. No. 16/108,730entitled “Methods And Devices For Activating Brown Adipose Tissue UsingElectrical Energy” (now U.S. Pat. No. 10,207,102) filed Aug. 22, 2018,which claims priority to U.S. patent application Ser. No. 14/584,066entitled “Methods And Devices For Activating Brown Adipose Tissue UsingElectrical Energy” (now U.S. Pat. No. 10,080,884) filed Dec. 29, 2014,which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods and devices for activatingbrown adipose tissue using electrical energy.

BACKGROUND OF THE INVENTION

Obesity is becoming a growing concern, particularly in the UnitedStates, as the number of people with obesity continues to increase andmore is learned about the negative health effects of obesity. Severeobesity, in which a person is 100 pounds or more over ideal body weight,in particular poses significant risks for severe health problems.Accordingly, a great deal of attention is being focused on treatingobese patients.

Surgical procedures to treat severe obesity have included various formsof gastric and intestinal bypasses (stomach stapling), biliopancreaticdiversion, adjustable gastric banding, vertical banded gastroplasty,gastric plications, and sleeve gastrectomies (removal of all or aportion of the stomach). Such surgical procedures have increasingly beenperformed laparoscopically. Reduced postoperative recovery time,markedly decreased post-operative pain and wound infection, and improvedcosmetic outcome are well established benefits of laparoscopic surgery,derived mainly from the ability of laparoscopic surgeons to perform anoperation utilizing smaller incisions of the body cavity wall. However,such surgical procedures risk a variety of complications during surgery,pose undesirable post-operative consequences such as pain and cosmeticscarring, and often require lengthy periods of patient recovery.Patients with obesity thus rarely seek or accept surgical intervention,with only about 1% of patients with obesity being surgically treated forthis disorder. Furthermore, even if successfully performed and initialweight loss occurs, surgical intervention to treat obesity may notresult in lasting weight loss, thereby indicating a patient's need foradditional, different obesity treatment.

Nonsurgical procedures for treating obesity have also been developed.However, effective therapies for increasing energy expenditure and/oraltering a patient's metabolism, e.g., a basal metabolic rate, leadingto improvements in metabolic outcomes, e.g., weight loss, have focusedon pharmaceutical approaches, which have various technical andphysiological limitations.

It has been recognized in, for example, U.S. Pat. No. 6,645,229 filedDec. 20, 2000 and entitled “Slimming Device,” that brown adipose tissue(BAT) plays a role in the regulation of energy expenditure and thatstimulating BAT can result in patient slimming. BAT activation isregulated by the sympathetic nervous system and other physiological,e.g., hormonal and metabolic, influences. When activated, BAT removesfree fatty acids (FFA) and oxygen from the blood supply for thegeneration of heat. The oxidative phosphorylation cycle that occurs inthe mitochondria of activated BAT is shown in FIGS. 1 and 2.

Accordingly, there is a need for improved methods and devices fortreating obesity and in particular for activating BAT.

SUMMARY OF THE INVENTION

The present invention generally provides methods and devices foractivating brown adipose tissue using electrical energy. In oneembodiment, a medical method is provided that includes positioning adevice in contact with tissue of a patient proximate to a depot of BAT,and activating the device to transcutaneously deliver an electricalsignal to the patient so as to activate a first nerve type in the BATwithout activating a second, different nerve type in the BAT. The firstnerve type can have a smaller diameter than the second nerve type. Theelectrical signal can have a peak current that is at least about 50 mA.

The method can vary in any number of ways. For example, the first nervetype can include sympathetic nerves, and the second nerve type caninclude parasympathetic nerves. For another example, the first nervetype can include sympathetic nerves, and the second nerve type caninclude sensory nerves. For yet another example, the electrical signalcan have a peak current in a range of about 50 mA to 100 mA. For anotherexample, the electrical signal can have a current of at least 10 mA. Forstill another example, the electrical signal can have a pulse width lessthan about 400 μs. For another example, the electrical signal iscontinuously delivered to the patient for at least one day. For stillanother example, positioning the device can include positioning at leasta partial portion of the device external to the patient, and the methodcan include, after the delivering of the electrical signal so as toactivate the first nerve type in the BAT, removing the device from beingin contact with the tissue of the patient, repositioning the device incontact with tissue of the patient proximate to a different depot ofBAT, and activating the device to deliver a second electrical signal tothe patient so as to activate the first nerve type in the differentdepot of BAT without activating a second, different nerve type in thedifferent depot of BAT.

In another embodiment, a medical method is provided that includespositioning a device in contact with tissue of a patient proximate to adepot of BAT, and activating the device to deliver an electrical signalto the patient so as to activate unmyelinated neurons in the BAT withoutactivating myelinated neurons in the BAT. The electrical signal can havea current of at least 10 mA.

The method can have any number of variations. For example, themyelinated neurons can have a diameter in a range of about 2 μm to 6 μm.For another example, a peak current of the electrical signal can be in arange of about 50 mA to 100 mA. For yet another example, the electricalsignal can have a pulse width less than about 400 μs. For anotherexample, positioning the device can include transcutaneously applyingthe device to an exterior skin surface of the patient. For yet anotherexample, positioning the device can include subcutaneously positioning apartial portion of the device within the patient. For still anotherexample, positioning the device can include implanting the deviceentirely within the patient. For another example, the device is incontinuous direct contact with the tissue of the patient for at leastone day with the device continuously delivering the electrical signal tothe patient for the at least one day.

In another aspect, a medical apparatus is provided that in oneembodiment includes at least one electrode configured to directlycontact a tissue of a patient proximate to a depot of BAT and to deliveran electrical signal to the patient so as to activate a first nerve typein the BAT without activating a second, different nerve type in the BAT.The first nerve type can have a smaller diameter than the second nervetype. The apparatus can also include at least one signal generator inelectronic communication with the at least one electrode and configuredto generate the electrical signal delivered by the at least oneelectrode.

The apparatus can have any number of variations. For example, anentirety of the apparatus can be configured to be implanted within thepatient with the at least one electrode directly contacting at least oneof the depot of BAT, the first nerve type, and the second nerve type.For another example, only a partial portion of the apparatus can beconfigured to be implanted within the patient. For yet another example,the at least one electrode can be configured to be positioned entirelyexternal to the patient and be positioned on a skin surface of thepatient.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a schematic view of an oxidative phosphorylation cycle thatoccurs in mitochondria within BAT cells;

FIG. 2 is a schematic view of BAT mitochondria showing an oxidativephosphorylation cycle that occurs in the mitochondria;

FIG. 3 is a schematic view of PET-CT images showing the locations of BATdepots in a patient subject to a cold environment and in the patient ina normal, warm environment;

FIG. 4 is a transparent view of a portion of a human neck, chest, andshoulder area with a shaded supraclavicular region;

FIG. 5 is a graph showing voltage v. time for a generic electricalsignal;

FIG. 6 is a graph showing voltage v. time for a generic electricalsignal including a low frequency modulating signal and a high frequencycarrier signal;

FIG. 7 is a front view of a body showing one embodiment of an electricalstimulation device positioned on opposite sides of the body's sagittalplane;

FIG. 8 is a schematic view of one embodiment of a transcutaneous devicefor neuromodulating BAT;

FIG. 9 is a plurality of graphs showing exemplary waveforms generated bythe transcutaneous device of FIG. 8;

FIG. 10 is a schematic view of one embodiment of an implantable devicefor neuromodulating BAT;

FIG. 11 is a plurality of graphs showing exemplary waveforms generatedby the implantable device of FIG. 10;

FIG. 12 is a schematic view of a PET-CT image showing the locations ofBAT depots in a subject to a cold environment in an experiment;

FIG. 13 is a graph showing an electroneurography graph of voltage versustime for a square wave in a transcutaneous stimulation of a tibial nervein an animal model; and

FIG. 14 is a graph showing an electroneurography graph of voltage versustime for SNS in a transcutaneous stimulation of a tibal nerve in ananimal model.

DETAILED DESCRIPTION OF THE INVENTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Methods and Devices

Various exemplary methods and devices are provided for activating brownadipose tissue (BAT) using electrical energy. In general, the methodsand devices can facilitate activation of BAT to increase thermogenesis,e.g., increase heat production and energy expenditure in the patient,which over time can lead to one or more of weight loss, a change in themetabolism of the patient, e.g., increasing the patient's basalmetabolic rate, and improvement of comorbidities associated withobesity, e.g., Type II diabetes, high blood pressure, etc. In anexemplary embodiment, a medical device is provided that activates BAT byelectrically stimulating nerves that activate the BAT and/orelectrically stimulating brown adipocytes directly, thereby increasingthermogenesis in the BAT and inducing weight loss, increasing metabolicrate, and/or improving one or more comorbidities through energyexpenditure. In this way, weight loss, increased metabolic rate, and/orcomorbidity improvement can be induced without performing a majorsurgical procedure, without relying on administration of one or morepharmaceuticals, without relying on cooling of the patient, and withoutsurgically altering a patient's stomach and/or other digestive organs.

The electrical energy applied to BAT can include an electrical signalconfigured to target sympathetic nerves that can directly innervate BAT.The electrical signal can be configured to target the sympathetic nervesusing fiber diameter selectivity. In other words, the electrical signalcan be configured to activate nerve fibers having a first diameterwithout activating nerve fibers having diameters different than thefirst diameter. Sympathetic nerves include postganglionic unmyelinated,small diameter fibers, while parasympathetic nerves that can directlyinnervate BAT include preganglionic myelinated, larger diameter fibers.The electrical signal can be configured to target and activate thepostganglionic unmyelinated, small diameter fibers without activatingthe preganglionic myelinated, larger diameter fibers. The energyrequired to activate the postganglionic unmyelinated, small diameterfibers (e.g., the sympathetic nerves) is greater than the energyrequired to activate the preganglionic myelinated, larger diameterfibers (e.g., the parasympathetic nerves). The energy of the electricalsignal can be relatively high so as to activate the sympathetic fiberswithout activating the parasympathetic nerves. The electrical signal canthus effectively activate the BAT because, as will be appreciated by aperson skilled in the art, stimulating the sympathetic nervous systemthat includes sympathetic nerves can effectively activate BAT.

The electrical signal applied to BAT that is configured to targetsympathetic nerves can include a simple signal including a single wave(e.g., a square wave, etc.), or the electrical signal applied to BATthat is configured to target sympathetic nerves can include a pluralityof waves (e.g., a carrier signal and a modulating signal). Embodimentsof electrical signals to activate BAT are discussed further below andare described in U.S. Pat. Pub. No. 2011/0270360 entitled “Methods AndDevices For Activating Brown Adipose Tissue Using Electrical Energy”filed Dec. 29, 2010, which is hereby incorporated by reference in itsentirety.

The diameter of sympathetic nerve fibers can be about 2 μm. A personskilled in the art will appreciate that the diameter of a sympatheticnerve fiber may not be precisely 2 μm but nevertheless be considered tobe 2 μm due to one or more factors, such as precision of instrumentsused to measure fiber diameters. Sympathetic nerve fibers that branchforming small diameter axon with intermittent varicosities can have adiameter that is less than 2 μm. The electrical signal applied to BATcan thus be configured to target nerve fibers having a diameter of about2 μm or less.

Parasympathetic and sympathetic nerves form an efferent pathwayincluding preganglionic and postganglionic neurons. Second-orderpostganglionic neurons synapse on smooth and cardiac muscle and alsocontrol glandular secretion. In addition to preganglionic andpostganglionic neurons, control systems of the autonomic nervous system(ANS) that includes the sympathetic and parasympathetic nervous systemsalso involve supraspinal controlling and integrative neuronal centers;supraspinal, spinal, ganglionic, and peripheral interneurons; andafferent neurons. Afferent neurons have cell bodies in the dorsal rootganglia or cranial nerve somatic sensory ganglia. Afferent axons travelin somatic peripheral nerves or along with autonomic efferent nerves.

The parasympathetic preganglionic component of the ANS has a supraspinaland spinal portion. Parasympathetic preganglionic neurons are found infour parasympathetic brain stem nuclei: nucleus Edinger-Westphal,superior salivatory nucleus, inferior salivatory nucleus, and the dorsalvagal complex of the medulla. Their axons exit via cranial nerves 3(oculomotor); 7 (facial nerve); 9 (glossopharyngeal nerve); and 10(vagus nerve) respectively. Parasympathetic preganglionic neurons arealso found in the intermediolateral (IML) cell column of the sacralspinal cord in segments S2-S4 and exit the central nervous system (CNS)via the sacral ventral roots and the spinal nerves and then continue tothe pelvic viscera as the pelvic nerve. The sacral preganglionicparasympathetic efferent axons of the pelvic nerve synapse withpostganglionic parasympathetic neurons in the ganglia of the pelvicplexus. Postganglionic axons innervate the descending colon, rectum,urinary bladder, and sexual organs.

The sympathetic preganglionic component of the ANS is purely spinal.Sympathetic preganglionic neurons (SPNs) are found in the IML cellcolumn of the thoracic and lumbar spinal cord in segments T1-L2 and exitthe CNS via the thoracolumbar ventral roots. The sympathetic segmentaloutflow can vary, and the outflow can start as high as C8 or as low asT2 and end at L1 or L3. The thinly myelinated preganglionic fibers exitvia the ventral roots as the white rami communicantes. Many sympatheticpreganglionic fibers synapse in the paravertebral ganglia, which arepaired and lie next to the spine from the cervical to the sacralsegments. There are three cervical paravertebral ganglia: the superiorcervical ganglion, the middle cervical ganglion, and the stellateganglion. There are usually eleven thoracic ganglia, four lumbarganglia, and four or five sacral ganglia. Sympathetic preganglionicaxons can synapse in paravertebral ganglia at the segment of their exitor can pass up or down several segments of the sympathetic chain beforesynapsing. One sympathetic preganglionic axon will synapse with severalpostganglionic neurons. Postganglionic axons are unmyelinated, smalldiameter fibers that leave the paravertebral ganglia via the gray ramicommunicantes and exit via the segmental spinal nerves.

Some sympathetic preganglionic axons pass through the paravertebralganglia without synapsing and constitute the splanchnic nerves thatinnervate three prevertebral ganglia: celiac ganglion, superiormesenteric ganglion, and inferior mesenteric ganglion (IMG), as well asthe adrenal medulla. Postsynaptic axons from the prevertebral gangliacourse to the abdominal and pelvic viscera as the hypogastric,splanchnic, and mesenteric plexuses.

Sweat glands, piloerector muscles, and most small blood vessels receiveonly sympathetic innervation. Diffuse sympathetic nervous systemdischarge results in pupillary dilatation, increased heart rate andcontractility, bronchodilation, vasoconstriction of the mesentericcirculation, and vasodilation of skeletal muscle arterioles. This is the“fight or flight” defense reaction.

Supraspinal neurons involved in the control systems of the ANS arelocated in the nucleus of the tractus solitarius (NTS), nucleusambiguus, dorsal motor nucleus of vagus, dorsal raphe nucleus, medullaryreticular formation nuclei, locus ceruleus, hypothalamus, limbic system,and the primary sensory and motor cortex. The hypothalamus has uncrossedsympathetic descending pathways to the midbrain, lateral pons, andmedullary reticular formation. Descending reticulospinal pathways fromthe pons and medulla to interneurons in the spinal cord influence theIML cells. The NTS receives afferents from the viscera and functions asan integrating center for reflex activity as well as a relay station tothe hypothalamus and limbic systems.

At the effector organs, sympathetic ganglionic neurons releasenoradrenaline (norepinephrine), along with other cotransmitters such asadenosine triphosphate (ATP), to act on adrenergic receptors, with theexception of the sweat glands and the adrenal medulla. Acetylcholine isthe preganglionic neurotransmitter for both divisions of the ANS, aswell as the postganglionic neurotransmitter of parasympathetic neurons.Nerves that release acetylcholine are said to be cholinergic. In theparasympathetic system, ganglionic neurons use acetylcholine as aneurotransmitter, to stimulate muscarinic receptors. At the adrenalcortex, there is no postsynaptic neuron. Instead, the presynaptic neuronreleases acetylcholine to act on nicotinic receptors. Stimulation of theadrenal medulla releases adrenaline (epinephrine) into the bloodstreamwhich will act on adrenoceptors, producing a widespread increase insympathetic activity.

Following a surgical procedure to treat obesity such as Roux-en-Ygastric bypass (RYGB), a patient can lose weight due to an increase inenergy expenditure, as demonstrated in a rodent model for example inStylopoulos et al., “Roux-en-Y Gastric Bypass Enhances EnergyExpenditure And Extends Lifespan In Diet-Induced Obese Rats,” Obesity 17(1 Oct. 2009), 1839-47. Additional data from Stylopoulos et al. (notpublished in the previous article or elsewhere as of the filing date ofthe present application) indicates that RYGB is also associated withincreased levels of uncoupling protein 1 (UCP1), which is an uncouplingprotein in mitochondria of BAT, as well as with a significant reductionin the size of fat stores within BAT and an increased volume of BAT. Itthus appears that RYGB causes activation of BAT, although as discussedabove, surgical procedures to treat obesity, such as gastric bypass,risk if not necessarily cause a variety of undesirable results in atleast some patients. Devices and methods to activate BAT without a majorsurgical procedure like RYGB but instead with electrical nervestimulation to increase energy expenditure are therefore provided.

One characteristic of BAT that distinguishes it from white adiposetissue (WAT) stores is the high number of mitochondria in a single BATcell. This characteristic makes BAT an excellent resource for burningenergy. Another distinguishing characteristic of BAT is that whenactivated, UCP1 is utilized to introduce inefficiency into the processof adenosine triphosphate (ATP) creation that results in heatgeneration. Upregulation of UCP1 is therefore a marker of BATactivation.

Activation of brown adipocytes leads to mobilization of fat storeswithin these cells themselves. It also increases transport of FFA intothese cells from the extracellular space and bloodstream, particularlywhen the local reserves that are associated with BAT are depleted. FFAsin the blood are derived primarily from fats metabolized and releasedfrom adipocytes in WAT as well as from ingested fats. Stimulation of thesympathetic nervous system is a major means of physiologicallyactivating BAT. Sympathetic nerve stimulation also induces lipolysis inWAT and release of FFA from WAT into the bloodstream to maintain FFAlevels. In this way, sympathetic stimulation leads ultimately to thetransfer of lipids from WAT to BAT followed by oxidation of these lipidsas part of the heat generating capacity of BAT. This activation of brownadipocytes can also lead to improvements in diabetes related markers.

The controlled activation of BAT can be optimized, leading to weightloss, increased metabolic rate, and/or comorbidity improvement, byreducing the stores of triglycerides in WAT. A person skilled in the artwill appreciate that exposure to cold temperature leads to theactivation of BAT to help regulate body temperature. This knowledgeallows the location of BAT to be readily assessed using positronemission tomography-computed tomography (PET-CT) imaging. FIG. 3 showsscans of a patient subjected to a cold environment (left two images) andthe same patient scanned in a normal, warm environment (right twoimages). Shown in black are regions of intense glucose uptake—namely,the brain, the heart, the bladder, and in the cold environment, BAT.However these images show the locations of BAT depots—namely the nape ofthe neck, the supraclavicular region, over the scapula, alongside thespinal cord, and around the kidneys as referenced by, for example,Rothwell et al, “A Role For Brown Adipose Tissue In Diet-InducedThermogenesis,” Nature, Vol. 281, 6 Sep. 1979, and Virtanen et al.,“Functional Brown Adipose Tissue in Healthy Adults,” The New EnglandJournal of Medicine, Vol. 360, No. 15, Apr. 9, 2009, 1518-1525.

A person skilled in the art will appreciate that adult humans havesubstantial BAT depots, as indicated, for example, in J. M. Heaton, “TheDistribution Of Brown Adipose Tissue In The Human,” J Anat., 1972 May,112(Pt 1): 35-39, and W. D. van Marken Lichtenbelt et al,“Cold-Activated Brown Adipose Tissue in Healthy Men,” N. Engl. J. Med.,2009 April, 360, 1500-1508. A person skilled in the art will alsoappreciate that BAT is heavily innervated by the sympathetic nervoussystem, as indicated, for example, in Lever et al., “Demonstration Of ACatecholaminergic Innervation In Human Perirenal Brown Adipose Tissue AtVarious Ages In The Adult,” Anat Rec., 1986 July, 215(3): 251-5, 227-9.Further, “[t]he thin unmyelinated fibers that contain norepinephrine(and not NPY) are those that actually innervate the brown adipocytesthemselves. They form a dense network within the tissue, being incontact with each brown adipocyte (bouton-en-passant), and their releaseof norepinephrine acutely stimulates heat production and chronicallyleads to brown adipose tissue recruitment.” B. Cannon, and J.Nedergaard, “Brown Adipose Tissue: Function And PhysiologicalSignificance,” Physiol Rev., 2004: 84: 277-359.

Sympathetic nerves innervating BAT can be neuromodulated to activateUCP1 and hence increase energy expenditure through heat dissipationthrough transcutaneous and/or direct neuromodulation of sympatheticnerves innervating BAT. Transcutaneous and direct neuromodulation areeach discussed below in more detail.

In some embodiments, transcutaneous and/or direct neuromodulation ofsympathetic nerves innervating BAT can be combined with one or moretreatments, before and/or after transcutaneous and/or direct stimulationof BAT, which can help encourage BAT activation and/or increase anamount of BAT in a patient. One or more techniques to activate BAT canbe used at a time, e.g., a patient can be cooled and electricallystimulated. For a non-limiting example of such a treatment, exposure tocold temperature can lead to the activation of BAT to help regulate bodytemperature. Exemplary embodiments of using cooling to activate BAT aredescribed in U.S. application Ser. No. 13/977,555 entitled “Methods AndDevices For Activating Brown Adipose Tissue With Cooling” filed Jun. 28,2013, which is hereby incorporated by reference in its entirety. Foranother non-limiting example of such a treatment, BAT can be activatedusing light. Exemplary embodiments of using light to activate BAT aredescribed in more detail in U.S. Pat. Pub. No. 2014/0088487 entitled“Methods And Devices For Activating Brown Adipose Tissue Using Light”filed Jun. 28, 2013, which is hereby incorporated by reference in itsentirety. For yet another non-limiting example of such a treatment, BATcan be chemically stimulated. Exemplary embodiments of using one or morechemicals to activate BAT are described in more detail in U.S. Pat. Pub.No. 2014/0018767 entitled “Methods And Devices For Activating BrownAdipose Tissue With Targeted Substance Delivery” filed Jun. 28, 2013,which is hereby incorporated by reference in its entirety. For anothernon-limiting example of such a treatment, brown adipocytes can bemodified to increase activation of BAT, e.g., increasing a number of BATadipocytes or increasing activation of BAT by modifying brown adipocytesto express a gene that activates brown adipocytes, such as UCP1.Exemplary embodiments of using modifying brown adipocytes to increaseactivation of BAT are described in more detail in U.S. Pat Pub. No.2014/0199278 entitled “Brown Adipocyte Modification” filed Jun. 28,2013, which is hereby incorporated by reference in its entirety. Othernon-limiting examples of such a treatment include the patient beingheated, a magnetic field being targeted to a region of a patient, thepatient engaging in weight loss therapies, and/or a surgical procedurebeing performed on the patient, such as a procedure to induce weightloss and/or to improve metabolic function, e.g., glucose homeostatis,lipid metabolism, immune function, inflammation/anti-inflammatorybalance, etc. Non-limiting examples of such weight loss therapiesinclude a prescribed diet and prescribed exercise. Non-limiting examplesof such a surgical procedure include gastric bypass, biliopancreaticdiversion, a gastrectomy (e.g., vertical sleeve gastrectomy, etc.),adjustable gastric banding, vertical banded gastroplasty, intragastricballoon therapy, gastric plication, Magenstrasse and Mill, small boweltransposition, biliary diversion, vagal nerve stimulation,gastrointestinal barrier (e.g., duodenal endoluminal barrier, etc.), andprocedures that allow for removal of food from the gastrointestinaltract.

Combining one or more treatments, particularly a weight loss therapy ora weight loss surgical procedure which does not activate BAT, e.g., aprocedure other than RYGB, biliopancreatic diversion (BPD) with orwithout duodenal switch, or some duodenal or other intestinal barrier(e.g., a prescribed diet and/or exercise program, adjustable gastricbanding, vertical banded gastroplasty, sleeve gastrectomy, gastricplication, Magenstrasse and Mill, intragastric balloon therapy, someduodenal or other intestinal barrier, and small bowel transposition,with a means for acute or chronic activation of BAT such as the nervestimulation discussed herein, can result in desirable patient outcomesthrough a combined approach.

Because BAT activation may lead to an increase in body temperaturelocally, regionally, or systemically, transcutaneous and/or directstimulation of nerves innervating BAT can be combined with one or moreheat dissipation treatments, before and/or after transcutaneous and/ordirect stimulation of BAT. Non-limiting examples of such a heatdissipation treatment include inducing cutaneous/peripheralvasodilation, e.g., local or systemic administration of Alphaantagonists or blockers, direct thermal cooling, etc.

Whether BAT is activated directly and/or transcutaneously, target areasfor BAT nerve stimulation and/or direct stimulation of brown adipocytescan include areas proximate to BAT depots, e.g., a supraclavicularregion, the nape of the neck, over the scapula, alongside the spinalcord, near proximal branches of the sympathetic nervous system thatterminate in BAT depots, and around at least one of the kidneys. Any BATdepot can be selected for activation. For non-limiting example, in oneembodiment illustrated in FIG. 4, the device (not shown) can bepositioned proximate to an area over a scapula in a supraclavicularregion S. Identification of one or more BAT depots for activation can bedetermined on an individualized patient basis by locating BAT depots ina patient by imaging or scanning the patient using PET-CT imaging,tomography, thermography, MRI, or any other technique, as will beappreciated by a person skilled in the art. Non-radioactive basedimaging techniques can be used to measure changes in blood flowassociated with the activation of BAT within a depot. In one embodiment,a contrast media containing microbes can be used to locate BAT. Thecontrast media can be injected into a patient whose BAT has beenactivated. An energy sources such as low frequency ultrasound can beapplied to the region of interest to cause destruction of bubbles fromthe contrast media. The rate of refill of this space can be quantified.Increased rates of refill can be associated with active BAT depots. Inanother embodiment, a contrast media containing a fluorescent media canbe used to locate BAT. The contrast media can be injected into a patientwhose BAT has been activated. A needle based probe can be placed in theregion of interest that is capable of counting the amount of fluorescentcontrast that passes the probe. Increased counts per unit timecorrespond to increased blood flow and can be associated with activatedBAT depots. Because humans can have a relatively small amount of BAT andbecause it can be difficult to predict where BAT is most prevalent evennear a typical BAT depot such as the nape of the neck, imaging a patientto more accurately pinpoint BAT depots can allow more nerves innervatingBAT to be activated and with greater precision. Any number of BAT depotsidentified through patient imaging can be marked for future referenceusing a permanent or temporary marker. As will be appreciated by aperson skilled in the art, any type of marker can be used to mark a BATdepot, e.g., ink applied on and/or below the epidermis, a dye injection,etc. The marker can be configured to only be visible under speciallighting conditions such as an ultraviolet light, e.g., a black light.

Whether BAT is activated directly and/or transcutaneously, targetcellular areas for BAT nerve activation and/or direct activation ofbrown adipocytes can include cell surface receptors (e.g., TGR5, β₁AR,β₂AR, β₃AR, etc.), nuclear receptors (e.g., PPARγ, FXR, RXR, etc.),transcription co-activators and co-repressors (e.g., PGC1α, etc.),intracellular molecules (e.g., 2-deiodinase, MAP kinase, etc.), UCP1activators, individual cells and related components (e.g., cell surface,mitochondria, and organelles), transport proteins, PKA activity,perilipin and HSL (phospho PKA substrate), CREBP (cAMP responseelement-binding protein), adenosine monophosphate-activated proteinkinase (AMPK), bile acid receptors (e.g., TGR5, FGF15, FXR, RXR α,etc.), muscarinic receptors, etc.

In the course of treating a patient, BAT nerves and/or brown adipocytescan be neuromodulated at any one or more BAT depots directly orindirectly and can be neuromodulated simultaneously, e.g., two or moreBAT depots being concurrently activated, or activated sequentially,e.g., different BAT depots being activated at different times.Simultaneous neuromodulation of BAT can help encourage more and/orfaster energy expenditure. Sequential neuromodulation of BAT can helpprevent the “burning out” of target nerves and can help stimulate thecreation of new BAT cells. Sequential nerve neuromodulation can includeactivating the same BAT depot more than once, with at least one otherBAT depot being neuromodulation before activating a previously activatedBAT depot. Simultaneous and/or sequential stimulation can help preventtachypylaxis.

The electrical signal, whether transcutaneously or directly delivered,can be configured in a variety of ways. The stimulation “on” timeamplitude can be higher for shorter periods and increased or decreasedfor longer periods of application. The electrical signal can have any“geometry” of the applied voltage, e.g., square waves, ramp waves, sinewaves, triangular waves, and waveforms that contain multiple geometries.FIG. 5 illustrates amplitude, pulse width, activation signal pulsefrequency, duration of signal train, and a time between start of signaltrains for a generic (without any specified numerical parameters)electrical signal. For example, the electrical signal can have a currentof at least about 50 mA, e.g., in a range of about 50 mA to 500 mA, in arange of about 50 mA to 100 mA, etc. For another example, the electricalsignal can have a pulse width in a range of about 400 μs to 1000 μs. Foryet another example, the electrical signal can have a frequency in arange of about 1 Hz to 50 Hz. For another example, the electrical signalcan have a voltage having an amplitude in a range of about 1 to 20 V,e.g., about 10 V, e.g., about 4 V, about 7 V, etc.; a current having anamplitude in a range of about 2 to 6 mA, e.g., about 3 mA; a pulse widthin a range about 10 μs to 40 ms, e.g., about 0.1 ms, about 2 ms, about20 ms, etc.; an activation signal pulse frequency in a range of about0.1 to 40 Hz, e.g., about 6 Hz or in a range of about 1 to 20 Hz; and aduration of signal train in a range of about 1 second to continuous,e.g., about 30 seconds, etc. Specific parameters for an electricalsignal can be different based on where the electrical signal isdelivered, e.g., based on whether an electrode delivering the electricalsignal is transcutaneously placed or is implanted. In an exemplaryembodiment of direct and/or subcutaneous stimulation of myelinatedfibers, the electrical signal can have a current amplitude in a range ofabout 0.1 to 10 mA and a pulse width in a range of about 50 to 300 μsec.In general, a charge needed to stimulate myelinated fibers is less thana charge needed to stimulate unmyelinated fibers. In an exemplaryembodiment of direct and/or subcutaneous stimulation of unmyelinatedfibers, the electrical signal can have a current amplitude greater thanand a pulse width at least as high as when applied to myelinated fibers,e.g., the first electrical signal having a current amplitude of greaterthan 10 mA and a pulse width of at least 300 μsec (e.g., a pulse widthin a range of about 300 to 1000 μsec). In an exemplary embodiment oftranscutaneous stimulation of myelinated fibers, the electrical signalcan have a current amplitude of at least about 10 mA (e.g., in a rangeof about 10 to 100 mA) and a pulse width less than about 400 μsec. Ingeneral, current amplitudes above 100 mA can be uncomfortable for apatient. In an exemplary embodiment of transcutaneous stimulation ofunmyelinated fibers, the electrical signal can have a current amplitudeof at least about 50 mA (e.g., in a range of about 50 to 100 mA) and apulse width in a range of about 400 to 1000 μsec. As will be appreciatedby a person skilled in the art, the charge used to stimulate fibers canbe adjusted by adjusting the current amplitude and the pulse width toachieve a desired charge. In general, in adjusting the charge, reducingthe pulse width for the electrical signal can be beneficial overincreasing the pulse width since very long pulse widths could causedamage and/or discomfort to the patient. A person skilled in the artwill appreciate that a specific parameter may not have a precisenumerical value but nevertheless be considered to be “about” thatspecific numerical value due to one or more factors, such asmanufacturing tolerances of a device that generates a signal having thespecific parameter.

A time between start of signal trains for a noncontinuous electricalsignal delivered to BAT can be of any regular, predictable duration,e.g., hourly, daily, coordinated around circadian, ultradian, or othercycles of interest, etc., such as about ten minutes or about ninetyminutes, or can be of any irregular, unpredictable duration, e.g., inresponse to one or more predetermined trigger events, as discussedfurther below. Embodiments of continuously delivering an electricalsignal to BAT and embodiments of non-continuously delivering anelectrical signal to BAT are further described in U.S. Pat. Pub. No.2011/0270360 entitled “Methods And Devices For Activating Brown AdiposeTissue Using Electrical Energy” filed Dec. 29, 2010.

In one embodiment, the same electrical signal can be delivered to aparticular BAT depot, either continuously or sequentially. In anotherembodiment, a first electrical signal can be transcutaneously ordirectly delivered to a particular BAT depot, and then subsequently,either immediately thereafter or after a passage of a period of time, asecond, different electrical signal can be delivered to the sameparticular BAT depot. In this way, chances of a BAT depot adapting to aparticular electrical signal can be reduced, thereby helping to preventthe BAT depot from becoming less receptive to electrical stimulation.

Whether a continuous electrical signal or an intermittent electricalsignal is transcutaneously delivered, e.g., with a transdermal patch asdiscussed further below, or subcutaneously delivered via an at leastpartially implanted device, the electrical signal can include a lowfrequency modulating signal and a high frequency carrier signal.Generally, the high frequency carrier signal can be used to pass throughhigh impedance tissue (subcutaneous or transcutaneous) while themodulating signal can be used to activate nervous tissue and/orelectrically responsive brown adipocytes. The waveform can be generatedby modulating a carrier waveform with a pulse envelope. Properties ofthe carrier waveform such as amplitude, frequency, and the like, can bechosen so as to overcome the tissue impedance and the stimulationthreshold of the target nerve. The pulse envelope can be a waveformhaving a specific pulse width, amplitude and shape designed toselectively stimulate the target nerve. This waveform can be able topenetrate efficiently through tissue, such as skin, to reach the targetnerve with minimal loss in the strength of the electrical signal,thereby saving battery power that would otherwise have been used inseveral attempts to stimulate the target nerve with low frequencysignals. Moreover, only the target nerve is stimulated, and non-targetnerves, e.g., nerves associated with pain, are not stimulated.

Exemplary embodiments of methods and devices for applying a signalincluding a high frequency carrier signal are described in more detailin U.S. Pat. Pub. No. 2011/0270360 entitled “Methods And Devices ForActivating Brown Adipose Tissue Using Electrical Energy” filed Dec. 29,2010, U.S. Pat. Pub. No. 2009/0093858 filed Oct. 3, 2007 and entitled“Implantable Pulse Generators And Methods For Selective NerveStimulation,” U.S. Pat. Pub. No. 2005/0277998 filed Jun. 7, 2005 andentitled “System And Method For Nerve Stimulation,” and U.S. Pat. Pub.No. 2006/0195153 filed Jan. 31, 2006 and entitled “System And Method ForSelectively Stimulating Different Body Parts.”

The low frequency modulating signal and a high frequency carrier signalcan each have a variety of values and configurations. The low frequencymodulating signal can be, e.g., a signal having an activation signalpulse frequency in a range of about 0.1 to 100 Hz, e.g., in a range ofabout 0.1 to 40 Hz, e.g., less than about 10 Hz. The high frequencycarrier signal can be, e.g., in a range of about 10 to 400 kHz, e.g., ina range of about 200 to 250 kHz. Pulse widths can also vary, e.g., be ina range of about 10 μs to 10 ms, e.g., less than about 2 ms. In oneexemplary embodiment, the electrical signal can have a modulating signalin a range of about 2 to 15 Hz, e.g., about 6 Hz, a carrier frequency ofabout 210 kHz, and a pulse width in a range of about 0.1 to 2 ms. FIG. 6illustrates a generic (without any specified numerical parameters)electrical signal including a low frequency modulating signal L and ahigh frequency carrier signal H.

Generally, low frequency signals can cause activation of Types A and Bfibers, e.g., myelinated neurons, and Type C fibers, e.g., unmyelinatedneurons. The signal to activate Type C fibers can be greater than, e.g.,a longer pulse width and a higher current amplitude, than a signal toactivate Type A and B fibers. Postganglionic fibers innervating BATdepots likely include Type C fibers, thereby allowing a BAT depot to beactivated by a low frequency signal, e.g., a signal less than about 10Hz and having a pulse width greater than about 300 μs. Preganglionicnerves such as small diameter, unmyelinated Type C fibers and smalldiameter, myelinated Type B fibers may also innervate BAT, thereby alsoallowing a BAT depot to be activated by a low frequency signal, e.g., asignal in a range of about 10 to 40 Hz and having a pulse width lessthan about 200 μs.

An electrical signal delivered to a BAT depot can be appliedcontinuously, in predetermined intervals, in sporadic or randomintervals, in response to one or more predetermined trigger events, orin any combination thereof. If the signal is continuously delivered tothe patient, particular care should be taken to ensure that the signaldelivered to the patient will not damage the target nerves or tissues.For one non-limiting example, nerve or tissue damage can be reduced, ifnot entirely prevented, by continuously delivering an electrical signalvia en electrode having a relatively large surface area to helpdistribute an electrical signal's energy between multiple nerves. Forelectrical signals delivered intermittently, nerve damage can bereduced, if not entirely prevented, by selecting an on/off ratio inwhich the signal is “off” for more time than it is “on.” Fornon-limiting example, delivering an electrical signal to BATintermittently with an on/off ratio of about 1:19, e.g., electricalsignals delivered for 30 seconds every ten minutes (30 seconds on/9.5minutes off), can help reduce or entirely prevent nerve damage.

The device delivering the electrical signal can be configured to respondto one or more predetermined trigger events, e.g., events that aresensed by or otherwise signaled to the device. Non-limiting examples oftrigger events include the patient eating, the patient resting (e.g.,sleeping), a threshold temperature of the patient (e.g., a temperaturein the stimulated BAT depot or a core temperature), a directionalorientation of the patient (e.g., recumbent as common when sleeping), achange in the patient's weight, a change in the patient's tissueimpedance, manual activation by the patient or other human (e.g., via anonboard controller, via a wired or wirelessly connected controller, orupon skin contact), a blood chemistry change in the patient (e.g., ahormonal change), low energy expenditure, menstrual cycles in women,medication intake (e.g., an appetite suppressant such as topiramate,fenfluramine, etc.), an ultradian or other circadian rhythm of thepatient, and a manually-generated or automatically-generated signal froma controller in electronic communication, wired and/or wireless, withthe device. In one embodiment, the patient eating can be determinedthrough a detection of heart rate variability, as discussed in moredetail in U.S. Pat. No. 8,696,616 filed on Dec. 29, 2010 entitled“Obesity Therapy And Heart Rate Variability” and U.S. Pat. Pub. No.2012/0172783 filed on Dec. 29, 2010 and entitled “Obesity Therapy AndHeart Rate Variability,” which are hereby incorporated by reference intheir entireties. The controller can be internal to the device, belocated external from but locally to device, or be located external andremotely from device. As will be appreciated by a person skilled in theart, the controller can be coupled to the device in any way, e.g.,hard-wired thereto, in wireless electronic communication therewith, etc.In some embodiments, multiple devices can be applied a patient, and atleast two of those devices can be configured to deliver an electricalsignal based on different individual trigger events or combinations oftrigger events.

Generally, transcutaneous stimulation of BAT can include applying adevice to an exterior skin surface of a patient proximate to a BAT depotand activating the device to deliver an electrical signal to the BATdepot. In this way, the electrical signal can activate the BAT proximateto the device by stimulating the nerves innervating the BAT and/or bystimulating brown adipocytes directly. As mentioned above, two or moretranscutaneous devices, same or different from one another, can besimultaneously applied to a patient, proximate to the same BAT depot orto different BAT depots. Although a patient can have two or moretranscutaneously applied devices and although the devices can beconfigured to simultaneously deliver electrical signals to BAT, thedevices can be configured such that only one delivers an electricalsignal at a time. As also mentioned above, a transcutaneous device canbe rotated to different BAT depots of a patient and deliver anelectrical signal to each of the BAT depots. Rotating a device betweentwo or more different locations on a patient's body and/or removing adevice from a patient when not in use can help prevent nerve or tissuedesensitization and/or dysfunction, can help reduce any adverse effectsof a device's attachment to the body, e.g., irritation from an adhesiveapplying a device to skin, and/or can help stimulate creation orreplication of new BAT in multiple locations on a patient's body. Fornon-limiting example, the device can be placed in varying positions onthe body to modulate the activity of different regions of BAT. In oneembodiment, the device can be worn on one side of the neck, e.g., theleft side, for a period of time and then on an opposite side of theneck, e.g., the right side, for the next time period, etc. In anotherembodiment, the device can be worn on an anterior side of a BAT depot,e.g., front of a left shoulder on one side of the patient's coronalplane, for a period of time and then on an opposite, posterior side ofthe BAT depot, e.g., back of the left shoulder on the opposite side ofthe patient's coronal plane, for the next period of time. In yet anotherembodiment, illustrated in FIG. 7, a device 10 can be worn proximate aBAT depot on one of a left and right side of a sagittal plane P in asupraclavicular region of a body 12 for a period of time and then thedevice 10 can be worn on the other of the left and right sides of thesagittal plane P in the supraclavicular region proximate to another BATdepot for the next period of time. Although the same device 10 is shownin FIG. 7 as being sequentially relocated to different tissue surface orskin positions on the body 12, as discussed herein, one or both of thedevices can be implanted and/or two separate devices can be used with apatient such that a first device is positioned at one location and asecond device is positioned at a second, different location.

In one embodiment, a transcutaneous device can be positioned in a firstlocation on a patient, e.g., a left supraclavicular region, for a firstpredetermined period of time, e.g., one week, and then relocated to asecond location on the patient, e.g., a right supraclavicular region,for a second predetermined period of time, e.g., one week. The first andsecond predetermined periods of time can be the same as or differentfrom one another. The first and second locations can mirror each other,e.g., on left and rights of a sagittal plane of the patient, or they cannon-mirror images of one another. During the first predetermined periodof time, the device can be configured to cycle in a diurnal patternduring waking hours between being “on” to electrically stimulate thepatient, e.g., a 30 minute dose of electrical stimulation having any ofthe parameters discussed herein, and being “off” without deliveringelectrical stimulation to the patient, e.g., a one hour period of nostimulation. The electrical signal, e.g., an electrical signal includingmodulating and carrier signals, delivered when the device is “on” can becontinuous, can ramp up at a start of the “on” time to a predeterminedmaximum level, such as a level set by a physician during an initialpatient visit, can ramp down at an end of the “on” time, and can besubstantially constant between the ramp up and ramp down times. Thesignal can ramp up and down in any amount of time, e.g., in less thanabout five minutes. Such a cycle can be repeated about twelve time perday during each of the first and second predetermined periods of time,and during any subsequent periods of time, e.g., repeatedly switchingthe device every other week between the first and second locations.

In another embodiment, a transcutaneous device can be positioned on anexterior skin surface of a patient and be configured to electricallystimulate the patient in a natural mimicking pattern for a time periodof at least one week. The device can be relocated to a differentlocation on the patient's skin and stimulate the patient at thedifferent location in the natural mimicking pattern for another timeperiod of at least one week. The device can continue being located andrelocated for any number of weeks. The electrical stimulation caninclude a fixed carrier frequency and a variable modulating frequencyconfigured to vary based on nutrient and mechanoreceptors that indicatethe patient eating. In other words, the modulating frequency can mimicstomach distension of the patient.

In still another embodiment, a transcutaneous device can be positionedon an exterior skin surface of a patient and be configured tointermittently electrically stimulate the patient at a constantintensity, e.g., cycle between an “on” configuration delivering anelectrical signal at the constant intensity to the patient and an “off”configuration without delivering any electrical signal to the patient.The delivered electrical signal can ramp up at a start of an “on” timeperiod to the constant intensity, and can ramp down at an end of the“on” time period from the constant intensity. The signal can ramp up anddown in any amount of time, such as ramp up for about ¼ of a total “on”time, deliver the signal at the constant intensity for about ½ of thetotal “on” time, and ramp down for about ¼ of the total “on” time. Inone embodiment, the device can ramp up from about 0 Hz to about 20 Hz inabout 15 minutes, stimulate at about 20 Hz for about 35 minutes, andramp down from about 20 Hz to about 0 Hz in about 10 minutes for a total“on” time of about 50 minutes.

The transcutaneous device used to transcutaneously activate BAT can havea variety of sizes, shapes, and configurations. Generally, the devicecan be configured to generate and/or deliver an electrical signal totissue at predetermined intervals, in response to a manual trigger bythe patient or other human, in response to a predetermined triggerevent, or any combination thereof. As will be appreciated by a personskilled in the art, and as discussed in more detail above and in U.S.Pat. Pub. No. 2009/0093858 filed Oct. 3, 2007 and entitled “ImplantablePulse Generators And Methods For Selective Nerve Stimulation,” the bodyattenuates low frequency signals requiring a high frequency signal fortransdermal passage. This high-frequency or carrier signal, inconjunction with a modulating low frequency wave can be applied by thetranscutaneous device to stimulate the nerves innervating BAT for FFA orother lipid consumption leading to loss of body fat and body weight,increased metabolic rate, and/or comorbidity improvement.

FIG. 8 illustrates one exemplary embodiment of a transcutaneous device200 in the form of a selective nerve stimulation patch housingconfigured to generate and deliver an electrical signal to tissue suchas BAT. The device 200 includes a circuitized substrate 202 configuredto generate electrical signals for stimulating tissue such as BAT. Thedevice 200 can include a suitable power source or battery 208, e.g., alithium battery, a first waveform generator 264, and a second waveformgenerator 266. The first and second waveform generators 264, 266 can beelectrically coupled to and powered by the battery 208. The waveformgenerators 264, 266 can be of any suitable type, such as those sold byTexas Instruments of Dallas, Tex. under model number NE555. The firstwaveform generator 264 can be configured to generate a first waveform orlow frequency modulating signal 268, and the second waveform generator266 can be configured to generate a second waveform or carrier signal270 having a higher frequency than the first waveform 268. As discussedherein, such low frequency modulating signals cannot, in and ofthemselves, pass through body tissue to effectively stimulate targetnerves. The second waveform 270 can, however, to overcome this problemand penetrate through body tissue. The second waveform 270 can beapplied along with the first waveform 268 to an amplitude modulator 272,such as the modulator having the designation On-Semi MC1496, which issold by Texas Instruments.

The modulator 272 can be configured to generate a modulated waveform 274that is transmitted to one or more electrodes 232 accessible at a bottomsurface of the circuitized substrate 202. Although FIG. 8 shows only oneelectrode 232, the device 200 can include two or more electrodes. Theelectrodes 232 can be configured to, in turn, apply the modulatedwaveform 274 to a target nerve to stimulate the target nerve. Asillustrated in FIGS. 8 and 9, the first waveform 268 can be a squarewave, and the second waveform 270 can be a sinusoidal signal. As will beappreciated by a person skilled in the art, modulation of the firstwaveform 268 with the second waveform 270 can results in a modulatedwaveform or signal 274 having the configuration shown in FIG. 9.Although the signals in FIG. 9 are illustrated as being biphasic, thesignals can be monophasic.

Various exemplary embodiments of transcutaneous devices configured toapply an electrical signal or other stimulation means to stimulatenerves are described in more detail in U.S. Pat. Pub. No. 2011/0270360entitled “Methods And Devices For Activating Brown Adipose Tissue UsingElectrical Energy” filed Dec. 29, 2010, U.S. Pat. Pub. No. 2009/0132018filed Nov. 16, 2007 and entitled “Nerve Stimulation Patches And MethodsFor Stimulating Selected Nerves,” U.S. Pat. Pub. No. 2008/0147146 filedDec. 19, 2006 and entitled “Electrode Patch And Method ForNeurostimulation,” U.S. Pat. Pub. No. 2005/0277998 filed Jun. 7, 2005and entitled “System And Method For Nerve Stimulation,” U.S. Pat. Pub.No. 2006/0195153 filed Jan. 31, 2006 and entitled “System And Method ForSelectively Stimulating Different Body Parts,” U.S. Pat. Pub. No.2007/0185541 filed Aug. 2, 2006 and entitled “Conductive Mesh ForNeurostimulation,” U.S. Pat. Pub. No. 2006/0195146 filed Jan. 31, 2006and entitled “System And Method For Selectively Stimulating DifferentBody Parts,” U.S. Pat. Pub. No. 2008/0132962 filed Dec. 1, 2006 andentitled “System And Method For Affecting Gastric Functions,” U.S. Pat.Pub. No. 2008/0147146 filed Dec. 19, 2006 and entitled “Electrode PatchAnd Method For Neurostimulation,” U.S. Pat. Pub. No. 2009/0157149 filedDec. 14, 2007 and entitled “Dermatome Stimulation Devices And Methods,”U.S. Pat. Pub. No. 2009/0149918 filed Dec. 6, 2007 and entitled“Implantable Antenna,” U.S. Pat. Pub. No. 2009/0132018 filed Nov. 16,2007 and entitled “Nerve Stimulation Patches And Methods For StimulatingSelected Nerves,” U.S. patent application Ser. No. 12/317,193 filed Dec.19, 2008 and entitled “Optimizing The Stimulus Current In A SurfaceBased Stimulation Device,” U.S. patent application Ser. No. 12/317,194filed Dec. 19, 2008 and entitled “Optimizing Stimulation Therapy Of AnExternal Stimulating Device Based On Firing Of Action Potential InTarget Nerve,” U.S. patent application Ser. No. 12/407,840 filed Mar.20, 2009 and entitled “Self-Locating, Multiple Application, And MultipleLocation Medical Patch Systems And Methods Therefor,” U.S. Pat. Pub. No.2011/0094773 filed Oct. 26, 2009 and entitled “Offset Electrode,” andU.S. Pat. No. 8,812,100 filed May 10, 2012 and entitled “A Device AndMethod For Self-Positioning Of A Stimulation Device To Activate BrownAdipose Tissue Depot In Supraclavicular Fossa Region.”

In an exemplary embodiment, the transcutaneous device can include anelectrical stimulation patch configured to be applied to an externalskin surface and to deliver an electrical signal to tissue below theskin surface, e.g., to underlying BAT. The patch can be configured togenerate its own electrical signal with a signal generator and/or todeliver an electrical signal received by the patch from a source inelectronic communication with the patch. The device can be wireless andbe powered by an on-board and/or external source, e.g., inductive powertransmission. The patch can be attached to the skin in any way, as willbe appreciated by a person skilled in the art. Non-limiting examples ofpatch application include using a skin adhesive locally (e.g., on patchrim), using a skin adhesive globally (e.g., on skin-contacting surfacesof the patch), using an overlying support (e.g., gauze with tapededges), using an adherent frame allowing interchangeability (e.g., abrace or an article of clothing), being subdermally placed with wirelessconnectivity (e.g., Bluetooth) or transdermal electrodes, and using anycombination thereof. Electrodes can include receiver circuitryconfigured to interact with a controller in electronic communicationwith the electrodes such that the controller can control at least somefunctions of the electrodes, e.g., on/off status of the electrodes andadjustment of parameters such as amplitude, frequency, length of train,etc.

In use, and as mentioned above, an electrical stimulation patch can beworn continuously or intermittently as needed. In a transcutaneousapplication, a patch such as one described in previously mentioned U.S.Pat. Pub. No. 2009/0132018, can be designed to transmit through the skinusing a dual waveform approach employing a first waveform designed tostimulated a nerve coupled with a high frequency carrier waveform. Thepatch can be placed proximate to a BAT depot, such as over the leftsupraclavicular region of the patient's back, for a predetermined amountof time, e.g., twelve hours, one day, less than one week, seven days(one week), one month (four weeks), etc., and can continuously deliveran electrical signal to the BAT. As mentioned above, the BAT depot canbe identified by imaging the patient prior to application of the patchproximate to the BAT depot. Seven days is likely the longest period anadhesive can be made to stick to the skin of a patient withoutmodification and can thus be a preferable predetermined amount of timefor patches applied to skin with an adhesive. After the predeterminedamount of time, the patch can be removed by a medical professional orthe patient, and the same patch, or more preferably a new patch, can beplaced, e.g., on the right supraclavicular region of the patient's backfor another predetermined amount of time, which can be the same as ordifferent from the predetermined amount of time as the first patchapplied to the patient. This process can be repeated for the duration ofthe treatment, which can be days, weeks, months, or years. In someembodiments, the process can be repeated until occurrence of at leastone threshold event, e.g., a predetermined amount of time, apredetermined physiological effect such as a predetermined amount ofweight lost by the patient, etc. If the same patch is relocated from afirst region, e.g., the left supraclavicular region, to a second region,right supraclavicular region, the patch can be reconditioned afterremoval from the first region and prior to placement at the secondregion. Reconditioning can include any one or more actions, as will beappreciated by a person skilled in the art, such as replacing one ormore patch components, e.g., a battery, an adhesive, etc.; cleaning thepatch; etc.

To more accurately simulate a weight loss surgery that has a continuousor chronic effect on a patient for an extended period of time, the patchcan be placed on a patient and continuously or chronically deliver anelectrical signal thereto for an extended, and preferably predetermined,amount of time. In an exemplary embodiment, the predetermined amount oftime can be at least four weeks. The electrical signal can be deliveredto same BAT depot for the predetermined amount of time, or two or moredifferent BAT depots can be stimulated throughout the predeterminedamount of time, e.g., left and right supraclavicular regions beingstimulated for alternate periods of seven days to total one month ofpredetermined time. Continued or chronic nerve stimulation to activateBAT can increase BAT energy expenditure over time and potentially inducemore or faster weight loss, a faster metabolic rate, and/or bettercomorbidity improvement than periodic or intermittent nerve stimulation.The electrical signal can be the same or can vary during the amount oftime such that the electrical signal is continuously and chronicallyapplied to the patient to provide 24/7 treatment mimicking the 24/7consequences of surgery. The continuous amount of time the patient iselectrically stimulated can be a total amount of continuous activationof any one BAT depot (e.g., activation of a single BAT depot),sequential activation of two or more BAT depots, simultaneous activationof two or more BAT depots, or any combination thereof. A total amount oftime of sequential activation of different BAT depots can be consideredas one extended amount of time despite different areas of BAT activationbecause activation of one BAT depot may cause the brain to signal forBAT activation in other BAT depots.

Generally, direct activation of BAT can include implanting a devicebelow the skin surface proximate to a BAT depot, e.g., within a BATdepot, and activating the device to deliver an electrical signal to thenerves innervating the BAT depot and/or to brown adipocytes directly.BAT itself is densely innervated, with each brown adipocyte beingassociated with its own nerve ending, which suggests that stimulatingthe BAT directly can target many if not all brown adipocytes anddepolarize the nerves, leading to activation of BAT. The sympatheticnerves that innervate BAT can be accessed directly through standardsurgical techniques, as will be appreciated by a person skilled in theart. The device can be implanted on a nerve or placed at or near a nervecell's body or perikaryon, dendrites, telodendria, synapse, on myelinshelth, node of Ranvier, nucleus of Schwann, or other glial cell tostimulate the nerve. While implanting such a device can require asurgical procedure, such implantation is typically relatively short,outpatient, and with greatly reduced risks from longer and morecomplicated surgical procedures such as gastric bypass. In an exemplaryembodiment, a stimulation device with at least two electrodes can be atleast partially implanted in the patient (e.g., an implanted electrodearray in communication with an external stimulator attached to apatient's skin; a percutaneous system such as a patch including astimulator and being in communication with percutaneous electrodescoupled to a conductor (e.g., a needle, a conductive gel, etc.); etc.),and more preferably entirely within the patient (e.g., an implantedmicrostimulator including an electrode array, an implantable pulsegenerator (IPG), and a lead connecting the electrode array and the IPG;an implanted microstimulator including an integrated electrode array andIPG; etc.). One example of the patch includes the Smartpatch (SPRTherapeutics, Cleveland, Ohio). One example of the electrode arrayincludes a flexible and flat array. A person skilled in the art willappreciate that any number of electrodes, e.g., one or more, can be atleast partially implanted in the patient. The leads of the at least oneelectrode can be implanted in a location sufficiently close to thenerves innervating the BAT so that when activated, the signal sentthrough the at least one electrode is sufficiently transferred toadjacent nerves, causing these nerves to depolarize. As mentioned above,electrodes can include receiver circuitry configured to interact with acontroller in electronic communication with the electrodes such that thecontroller can control at least some functions of the electrodes, e.g.,on/off status of the electrodes and adjustment of parameters such asamplitude, frequency, length of train, etc.

FIG. 10 illustrates one exemplary embodiment of an implantable device100 configured to generate and deliver an electrical signal to tissuesuch as BAT. The implantable device 100 can include a housing 102coupled to a suitable power source or battery 104, such as a lithiumbattery, a first waveform generator 106, and a second waveform generator110. As in the illustrated embodiment, the battery 104 and first andsecond waveform generators can be located within the housing 102. Inanother embodiment, a battery can be external to a housing and be wiredor wirelessly coupled thereto. The housing 102 is preferably made of abiocompatible material. The first and second waveform generators 106,110 can be electrically coupled to and powered by the battery 104. Thewaveform generators 106, 110 can be of any suitable type, such as thosesold by Texas Instruments of Dallas, Tex. under model number NE555. Thefirst waveform generator 106 can be configured to generate a firstwaveform or low frequency modulating signal 108, and the second waveformgenerator 110 can be configured to generate a second waveform or carriersignal 112 having a higher frequency than the first waveform 108. Thecarrier signal 112 can make it easier to stimulate BAT and/or nervesinnervating BAT by using less energy, and/or can make the electricalsignal more comfortable for the patient. As discussed herein, the firstwaveform 108 cannot easily, in and of themselves, pass through bodytissue to effectively stimulate target nerves. The second waveform 112can, however, help the electrical signal penetrate through body tissue.The second waveform 112 can be applied along with the first waveform 108to an amplitude modulator 114, such as the modulator having thedesignation On-Semi MC1496, which is sold by Texas Instruments.

The modulator 114 can be configured to generate a modulated waveform 116that is transmitted through a lead 118 to one or more electrodes 120.Four electrodes are illustrated, but the device 100 can include anynumber of electrodes having any size and shape. The lead 118 can beflexible, as in the illustrated embodiment. The electrodes 120 can beconfigured to, in turn, apply the modulated waveform 116 to a targetnerve 122 to stimulate the target nerve 122. As illustrated in FIGS. 6and 11, the first waveform 108 can be a square wave, and the secondwaveform 112 can be a sinusoidal signal. As will be appreciated by aperson skilled in the art, modulation of the first waveform 108 with thesecond waveform 112 can result in a modulated waveform or signal 116having the configuration shown in FIG. 6.

If an electrode is implanted under a patient's skin, a waveformtransmitted to the implanted electrode can include a modulating signalbut not include a carrier signal because, if the implanted electrode issufficiently near a BAT depot, the modulating signal alone can besufficient to stimulate the target. The waveform transmitted to animplanted electrode can, however, include both a modulating signal and acarrier signal.

Various exemplary embodiments of devices configured to directly apply anelectrical signal to stimulate nerves are described in more detail inU.S. Pat. Pub. No. 2011/0270360 entitled “Methods And Devices ForActivating Brown Adipose Tissue Using Electrical Energy” filed Dec. 29,2010, U.S. Pat. Pub. No. 2005/0177067 filed Jan. 26, 2005 and entitled“System And Method For Urodynamic Evaluation Utilizing Micro-ElectronicMechanical System,” U.S. Pat. Pub. No. 2008/0139875 filed Dec. 7, 2006and entitled “System And Method For Urodynamic Evaluation UtilizingMicro Electro-Mechanical System Technology,” U.S. Pat. Pub. No.2009/0093858 filed Oct. 3, 2007 and entitled “Implantable PulseGenerators And Methods For Selective Nerve Stimulation,” U.S. Pat. Pub.No. 2010/0249677 filed Mar. 26, 2010 and entitled “PiezoelectricStimulation Device,” U.S. Pat. Pub. No. 2005/0288740 filed Jun. 24, 2004and entitled, “Low Frequency Transcutaneous Telemetry To ImplantedMedical Device,” U.S. Pat. No. 7,599,743 filed Jun. 24, 2004 andentitled “Low Frequency Transcutaneous Energy Transfer To ImplantedMedical Device,” U.S. Pat. No. 7,599,744 filed Jun. 24, 2004 andentitled “Transcutaneous Energy Transfer Primary Coil With A High AspectFerrite Core,” U.S. Pat. No. 7,191,007 filed Jun. 24, 2004 and entitled“Spatially Decoupled Twin Secondary Coils For Optimizing TranscutaneousEnergy Transfer (TET) Power Transfer Characteristics,” and European Pat.Pub. No. 377695 published as International Pat. Pub. No. WO1989011701published Nov. 30, 2004 and entitled “Interrogation And Remote ControlDevice.”

In use, at least one electrode of an implantable electrical stimulationdevice can be placed in the area of a BAT depot and be coupled to asignal generator. As will be appreciated by a person skilled in the art,the signal generator can have a variety of sizes, shapes, andconfigurations, and can be external to the patient or implanted thereinsimilar to a cardiac pacemaker. The signal generator can create theelectrical signal to be delivered to the BAT and can be on continuouslyonce activated, e.g., manually, automatically, etc. The signal generatorcan be in electronic communication with a device external to thepatient's skin to turn it on and off, adjust signal characteristics,etc. The external device can be positioned near the patient's skin,e.g., using a belt, a necklace, a shirt or other clothing item,furniture or furnishings such as a chair or a pillow, or can be adistance away from the patient's skin, such as a source locatedelsewhere in the same room or the same building as the patient. Theelectrical stimulation device can include circuitry configured tocontrol an activation distance, e.g., how close to a power source theelectrical stimulation device must be to be powered on and/or begindelivering electrical signals. Correspondingly, the external device caninclude a transmitter configured to transmit a signal to the electricalstimulation device's circuitry. If implanted, the signal generator caninclude an internal power source, e.g., a battery, a capacitor,stimulating electrodes, a kinetic energy source such as magnetspositioned within wired coils configured to generate an electricalsignal within the coils when shaken or otherwise moved, etc. In oneembodiment, a battery can include a flexible battery, such as a Flexionbattery available from Solicore, Inc. of Lakeland, Fla. In anotherembodiment, a battery can include an injectable nanomaterial battery.The power source can be configured to be recharged by transcutaneousmeans, e.g., through transcutaneous energy transfer (TET) or inductivecoupling coil, and/or can be configured to provide power for an extendedperiod of time, e.g., months or years, regardless of how long the powersource is intended to provide power to the device. In some embodiments,a power source can be configured to provide power for less than anextended period of time, e.g., about 7 days, such as if a battery isreplaceable or rechargeable and/or if device real estate can beconserved using a smaller, lower power battery. In some embodiments, thesignal generator can include an electrode patch onboard configured togenerate a pulse, thereby eliminating a need for a battery.

The signal generator, and/or any other portion of the device or externaldevice, as will be appreciated by a person skilled in the art, can beconfigured to measure and record one or more physical signals relatingto the activation of BAT. For non-limiting example, the physical signalscan include voltage, current, impedance, temperature, time, moisture,salinity, pH, concentration of hormones or other chemicals, etc. Therecorded physical signals can be presented to the patient's physicianfor evaluation of system performance and efficacy of brown adiposeactivation. Also, the recorded physical signals can be used in aclosed-loop feedback configuration to allow the device, e.g., thecontroller, to dynamically adjust the electrical signal settings usedfor treatment.

In some embodiments, the BAT can be stimulated using a first electricalsignal and a second electrical signal. The first electrical signal canbe configured to stimulate the sympathetic nerves, and the secondelectrical signal can be configured to inhibit the other nerve type,e.g., to inhibit parasympathetic nerves and/or sensory nerves. Both ofthe first and second electrical signals can be deliveredtranscutaneously, which can facilitate application of the first andsecond electrical signals by allowing the first and second electricalsignals to be delivered using the same device applied transcutaneouslyto a patient. In another embodiment, both of the first and secondelectrical signals can be directly delivered, which can allow forunobtrusive BAT stimulation. Embodiments of applying a first electricalsignal to stimulate sympathetic nerves and applying a second electricalsignal to inhibit another nerve type are further described in U.S.application Ser. No. 14/584,046 filed on Dec. 29, 2014 entitled “MethodsAnd Devices For Inhibiting Nerves When Activating Brown Adipose Tissue,”which is hereby incorporated by reference in its entirety.

BAT and the nerves innervating BAT can each be stimulatedtranscutaneously (e.g., from outside a patient's body) or directly(e.g., by direct contact therewith). For a subcutaneous example, astimulator can be fully implanted within a patient to be in directcontact with a BAT depot to allow activation of the BAT depot. Foranother subcutaneous example, a stimulator can be fully implanted withina patient to be in direct contact with a nerve innervating a BAT depotto allow activation of the nerve. For a percutaneous example, astimulator can be partially implanted within a patient to be in directcontact with a BAT depot to allow activation of the BAT depot, e.g., anexternal skin patch including at least one electrode positioned on askin surface of a patient with at least one conductor extending from theat least one electrode and through the skin surface to the BAT depot, anexternal skin patch including at least one electrode positioned on askin surface of a patient with at least one light-emitting fiber opticwire extending from the at least one electrode and through the skinsurface to the BAT depot, etc. For another percutaneous example, astimulator can be partially implanted within a patient to be in directcontact with a nerve innervating a BAT depot to allow activation of thenerve, e.g., an external skin patch including at least one electrodepositioned on a skin surface of a patient with at least one conductiveneedle extending from the at least one electrode and through the skinsurface to the nerve, an external skin patch including at least oneelectrode positioned on a skin surface of a patient with at least onelight-emitting fiber optic wire extending from the at least oneelectrode and through the skin surface to the nerve, etc. For atranscutaneous example, a stimulator can be positioned external to apatient proximate a BAT depot to allow activation thereof, e.g., anexternal skin patch including at least one electrode positioned on askin surface of a patient with a conductive gel coupled to the at leastone electrode, etc.

The following examples provide methods and devices related to activatingBAT using electrical energy. The invention is not necessarily limited bywhat is particularly shown and described in the following examples,except as indicated by the appended claims.

Example 1

A study was performed using supraclavicular fat depots obtained from tenhuman cadaver subjects, six male and four female, with ages ranging fromtwenty-six to sixty-four (average age of 37.8 years), and with BMIsranging from twenty to thirty-one (average BMI of 23).

FIG. 12 shows the site 300 of tissue sample collection from thesubjects. FIG. 12 is a PET-CT scan of one of the subjects exposed tocold with black regions in the cold environment indicating BAT. BAT wasfound at this site 300 in seven of the ten cases. The three cases inwhich BAT was not found were in subjects over age sixty, therebyindicating a correlation of BAT presence in young people. As discussedfurther below, BAT was visually identified by confirming the presence ofUCP1 indicative of BAT, and the presence of sympathetic nerve fibers wasconfirmed by evaluating tyrosine hydroxylase (TH) to determine theamount of noradrenergic nerves and visualize their distribution.

To collect the tissue samples from each of the subjects, the chest wasopened and then the pericardial sac. Following the aorta pathway, theright brachiocephalic trunk was reached, and the supraclavicular fatdepots were dissected out. The tissues were immediately immersed inparaformaldehyde (PFA) 4% and kept overnight at 4° C. The following day,the samples were analyzed at the gross anatomy level.

The average dimension of individual samples was about 3 cm. Each one ofthe samples was divided in 3-4 pieces of 1 cm³ for the inclusion and thepreparation of histological samples and consequent immune-histochemicalanalysis.

The following steps are dehydratation and paraffin embedding of thetissues for sectioning. Sections from three different levels (500 μmapart) were hematoxylin and eosin stained to assess morphology,immunohistochemistry, and morphometry. All of the observations wereperformed with a Nikon Eclipse 80i light microscope (Nikon, Japan).

For each section level, 3 μm-thick dewaxed sections were treatedaccording to the avidin-biotin complex method (ABC) as follows: 1)endogenous peroxidase blocking with 3% hydrogen peroxide in methanol; 2)normal serum (1:75) for 20 min to reduce non-specific background; 3)incubation with primary antibodies (UCP1 and TH) overnight at 4° C.; 4)incubation with secondary IgG biotin-conjugated antibodies (1:200,Vector Labs, Burlingame, Calif.); 5) ABC kit (Vector Labs, Burlingame,Calif.); and 6) enzymatic reaction to reveal peroxidase with Sigma Fast3,3′-diaminobenzidine as the substrate. Finally, sections werecounterstained with hematoxylin and mounted in Eukitt (Fluka,Heidelberg, Germany).

Visible nerve bundles were observed to enter the fat pad. There weredissectible nerve bundles in close relationship with the fat collectedin the supraclavicular area (close to the large blood vessels found inthe lower neck). In the majority of the cases it was possible to isolatevisible bundles in the big pieces of tissues. The presence of BAT wasevaluated first by histology (H&E) searching for multilocular cells andthen confirmed by immune-staining toward UCP1. Different degree ofimmune-reactivity were found in different subjects, ranging from smallfoci slightly positive for UCP1 to larger amount strongly positive forUCP1. This variability could be related to individual differences but itcould be also in relation to different parameters (such as environmentalconditions as well as technical issues in relation to the timing of theautoptic examination). However, the macroscopic appearance of theadipose tissue without BAT presence, displayed some common features withthose in which BAT was actually found by histological examination. Thesetissues were built up by small lobuli and in particular the histologyallow to visualize the smaller size of adipocytes in the core of thetissue. This is a possible intermediate step in the process oftransformation of this tissue from a brown-like (found in youngerpeople) to more white-like morphology (found in older people) and thisis in agreement with recent data that describe a progressive loss of BATin specific locations. This transformation is likely mainly due to aphenotypic switch from BAT toward WAT (transdifferentiation).

Similar to animal models (e.g., interscapular BAT of rats), nerves withdifferent size in the human subjects were observed to enter the fat padat supraclavicular location. The nerves were visualized in closeproximity to the parenchyma and most likely have functional interactionwith the adipose tissue itself. The nerves below 100 μm in diameter arestrongly positive for TH (sympathetic fibers), and they are usuallyfound around the big blood vessels of the tissue in interlobularposition. Nerves above 100 μm (e.g., above 500 μm, in a range of800-1000 μm, etc.) were observed to usually be negative for TH. Some ofthese nerves were observed to be partially positive for TH, likelybecause in bigger nerves, different nerve fiber types are present indifferent proportion, bearing sympathetic and sensory fibers. Visualestimates were that 80-90% of the fibers with a maximum dimension of 100μm were positive for TH.

The observed sympathetic nerves were located in the BAT tissue. Thediameters of the nerve fibers directly innervating BAT were identifiedas 0.14 μm+/−0.05 μm (n=87) for the axon diameters and as 0.60 μm+/−0.05μm (n=238) for the varicosity diameters. The mean for all of the fiberswas identified as 0.47 μm+/−0.33 μm. Based on the structure of thesympathetic nervous system, the fibers that were measured arepostganglionic, small diameter, unmyelinated fibers.

Example 2

A study was performed examining transcutaneous stimulation of the tibialnerve of dogs. The latency of the electroneurogram (ENG) response wasused to calculate conduction velocity. The electrodes used were 1.25 in.diameter, round transcutaneous electrical nerve stimulation (TENS)electrodes covering a surface area was 7.92 cm². The fibers stimulatedhad diameters between 2 μm and 6 μm, e.g., myelinated fibers. Theelectrical signal applied had peak currents in a range of 50 mA to 300mA. A maximum peak current of 300 mA was applied safely in this studybecause the dogs were anesthetized. A maximum peak current of 300 mAwould ordinarily not be applied to a conscious subject, as it couldcause discomfort. A maximum peak current to conscious subjects can beabout 100 mA. Referring again to the study, the current density was in arange of 6.31 mA/cm² to 37.9 mA/cm². FIG. 13 shows electroneurography(ENG) of the square pulse applied. FIG. 14 shows the ENG of thesympathetic nervous system (SNS).

Table 1 below shows AB fiber thresholds for the tibial nervetranscutaneous stimulation.

TABLE 1 Peak Current Threshold (mA) A-fibers B-fibers Avg + SD A Avg +SD B Square 40 128 43 ± 31 85 ± 55 13 23 75 105 SNS 90 224 70 ± 47 134 ±98  16 30 103 147

Table 2 below shows that the transcutaneous stimulation was able tostimulate nerve fibers having diameters of less than 2 μm. In Table 2,20 m/s was the cutoff between A and B fibers, and the conversion factorused for the diameter was 5 m/s conduction velocity=1 μm diameter.Fibers of smaller diameter than those shown in Table 2 could bestimulated if electrode configuration is optimized.

TABLE 2 Electrode A/B Fiber Activity Conduction distance Cutoff latency(ms) velocity (m/s) Diameter (μm) Day Wave (cm) (ms) min max min max minmax Day 1 Square 12.5 6.25 4 13 9.6 31.3 1.9 6.3 SNS 4 13 9.6 31.3 1.96.3 Day 8 Square 11 5.5 3.2 9 12.2 34.4 2.4 6.9 SNS 3.7 7 15.7 29.7 3.15.9 Day 15 Square 12 6 3.5 9 13.3 34.3 2.7 6.9 SNS 3.7 8 15.0 32.4 3.06.5 Average 2.3 6.7 Square Average 2.7 6.2 SNS

CONCLUSION

The devices disclosed herein can be designed to be disposed of after asingle use, or they can be designed to be used multiple times. In eithercase, however, the device can be reconditioned for reuse after at leastone use. Reconditioning can include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces, and subsequent reassembly. In particular, the devicecan be disassembled, and any number of the particular pieces or parts ofthe device can be selectively replaced or removed in any combination.Upon cleaning and/or replacement of particular parts, the device can bereassembled for subsequent use either at a reconditioning facility, orby a surgical team immediately prior to a surgical procedure. Thoseskilled in the art will appreciate that reconditioning of a device canutilize a variety of techniques for disassembly, cleaning/replacement,and reassembly. Use of such techniques, and the resulting reconditioneddevice, are all within the scope of the present application.

Preferably, the invention described herein will be processed before use.First, a new or used instrument is obtained and if necessary cleaned.The instrument can then be sterilized. In one sterilization technique,the instrument is placed in a closed and sealed container, such as aplastic or TYVEK bag. The container and instrument are then placed in afield of radiation that can penetrate the container, such as gammaradiation, x-rays, or high-energy electrons. The radiation killsbacteria on the instrument and in the container. The sterilizedinstrument can then be stored in the sterile container. The sealedcontainer keeps the instrument sterile until it is opened in the medicalfacility.

It is preferred that device is sterilized. This can be done by anynumber of ways known to those skilled in the art including beta or gammaradiation, ethylene oxide, steam, and a liquid bath (e.g., cold soak).An exemplary embodiment of sterilizing a device including internalcircuitry is described in more detail in U.S. Pat. Pub. No. 2009/0202387filed Feb. 8, 2008 and entitled “System And Method Of Sterilizing AnImplantable Medical Device.” It is preferred that device, if implanted,is hermetically sealed. This can be done by any number of ways known tothose skilled in the art.

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

What is claimed is:
 1. A medical method, comprising: generating anelectrical signal that targets nerve fibers using fiber diameterselectivity; and delivering the electrical signal to brown adiposetissue (BAT), thereby activating nerve fibers having a first diameter.2. The method of claim 1, wherein the delivered electrical signal doesnot activate nerve fibers having diameters that are different than thefirst diameter.
 3. The method of claim 2, wherein the first diameter isless than about 2 μm; and the diameters that are different than thefirst diameter are greater than the first diameter and are less thanabout 6 μm.
 4. The method of claim 2, wherein the nerve fibers havingthe first diameter are unmyelinated nerve fibers, and the nerve fibershaving diameters that are different than the first diameter aremyelinated nerve fibers.
 5. The method of claim 1, wherein the firstdiameter is less than about 2 μm.
 6. The method of claim 5, wherein thenerve fibers having the first diameter are sympathetic nerve fibers. 7.The method of claim 6, wherein the delivered electrical signal does notactivate nerve fibers having diameters that are different than the firstdiameter; and the diameters that are different than the first diameterare greater than the first diameter and are less than about 6 μm.
 8. Themethod of claim 7, wherein the nerve fibers having diameters that aredifferent than the first diameter are parasympathetic nerve fibers. 9.The method of claim 1, wherein the electrical signal has a peak currentthat is in a range of about 50 mA to about 100 mA; and the electricalsignal has a pulse width less than about 400 μs.
 10. The method of claim1, wherein the electrical signal has a current of about 10 mA.
 11. Themethod of claim 1, wherein the generating includes continuouslygenerating the electrical signal for at least one day such that theelectrical signal is continuously delivered to the BAT for at least oneday.
 12. The method of claim 11, wherein the generating includescontinuously generating the electrical signal for less than four weeksand such that the electrical signal is continuously delivered to the BATfor less than four weeks.
 13. The method of claim 1, wherein thegenerating includes intermittently generating the electrical signal suchthat the electrical signal is intermittently delivered to the BAT.
 14. Amedical apparatus, comprising: a signal generator that generates theelectrical signal of claim 1 using fiber diameter selectivity; and anelectrode that delivers the electrical signal to the BAT.
 15. A medicalmethod, comprising: applying an electrical signal to brown adiposetissue (BAT) that targets nerves innervating the BAT using fiberdiameter selectivity.
 16. The method of claim 15, wherein the electricalsignal activates first nerves innervating the BAT and having a firstdiameter without activating nerves innervating the BAT that havediameters different than the first diameter.
 17. The method of claim 16,wherein the first diameter is less than about 2 μm; and the diametersdifferent than the first diameter are greater than the first diameterand are less than about 6 μm.
 18. The method of claim 16, wherein thefirst nerves are sympathetic nerves; and the nerves having diametersdifferent than the first diameter are parasympathetic nerves.
 19. Amedical apparatus, comprising: a signal generator that generates theelectrical signal of claim 15 using fiber diameter selectivity; whereinthe electrical signal is applied to the BAT using an electrode.
 20. Themethod of claim 19, wherein the first diameter is less than about 2 μm;and the diameters different than the first diameter are greater than thefirst diameter and are less than about 6 μm.